Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Abstract

While mitogen-activated protein kinase (MAPK) activation has been implicated in the pathogenesis of various glomerular diseases, including nephrotic syndrome (NS), its specific role in podocyte injury is not known. We hypothesized that MK-2, a downstream substrate of p38 MAPK, mediates the adverse effects of this pathway and that inhibition of MK-2 would protect podocytes from NS-related injury. Using cultured podocytes, we analyzed 1) the roles of MK-2 and p38 MAPK in puromycin aminonucleoside (PAN)-induced podocyte injury; 2) the ability of specific MK-2 and p38 MAPK inhibitors to protect podocytes against injury; 3) the role of serum albumin, known to induce podocyte injury, in activating p38 MAPK/MK-2 signaling; and 4) the role of p38 MAPK/MK-2 signaling in the expression of Cox-2, an enzyme associated with podocyte injury. Treatment with protein kinase inhibitors specific for both MK-2 (C23, a pyrrolopyridine-type compound) or p38 MAPK (SB203580) reduced PAN-induced podocyte injury and actin cytoskeletal disruption. Both inhibitors reduced baseline podocyte p38 MAPK/MK-2 signaling, as measured by the degree of phosphorylation of HSPB1, a downstream substrate of MK-2, but exhibited disparate effects on upstream signaling. Serum albumin activated p38 MAPK/MK-2 signaling and induced Cox-2 expression, and these responses were blocked by both inhibitors. Given the critical importance of podocyte injury to both NS and other progressive glomerular diseases, these data suggest an important role for p38 MAPK/MK-2 signaling in podocyte injury and identify MK-2 inhibition as a promising potential therapeutic strategy to protect podocytes in various glomerular diseases.

Comparison of Direct Action of Thiazolidinediones and Glucocorticoids on Renal Podocytes: Protection from Injury and Molecular Effects

“…Inhibition of p38 MAPK and possibly ERK1/2 in PAN and doxorubicin animal models of NS has been reported to suppress proteinuria and actin reorganization in podocytes (Koshikawa et al, 2005). In addition, we have shown that inhibiting either p38 MAPK or its downstream substrate MK2 prevents PAN-induced injury to podocytes (Pengal et al, 2011). Increased amounts of activated ERK and p38 MAPK 9.…”

APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases

“…In animal experimental models of glomerulopathies, activation of p38 MAPK or JNK is necessary for podocyte injury and proteinuria (40,43). Consistently, inhibition of these SAPKs prevents podocyte injury, suppresses proteinuria in animal models, and mitigates glomerulonephritis (41,(43)(44)(45)(46). Importantly, HIV-1 GP120-induced tubular epithelial apoptosis is also mediated by p38 MAPK signaling (47).…”

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

“…The same compound also improved cell viability in a nephrotic syndrome-related podocyte injury model by inhibition of MK2 activity and consequent reduction of COX-2 mRNA expression and Hsp27 phosphorylation. 48 On the other hand, 7 was used as MK2 inhibitor to study how senescence underwent an acceleration in fibroblasts from human WS, without reaching conclusive and unambiguous results. 49 …”